Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition

Kimbung, Siker; Biskup, Ewa; Johansson, Ida; Aaltonen, Kristina; Ottosson-Wadlund, Astrid; Gruvberger-Saal, Sofia K.; Cunliffe, Heather E.; Fadeel, Bengt; Loman, Niklas; Berglund, Pontus; Hedenfalk, Ingrid

doi:10.1016/j.canlet.2012.01.015

Cited by 43 publications

(25 citation statements)

References 39 publications

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“…2). An in vitro study tested this hypothesis by treating human breast cancer cells with the PARP-1 inhibitor AG14361 and the PI3K inhibitor LY294002 alone or in sequential combination using suboptimal concentrations (\IC50) [63]. Sequential combination of PARP and PI3K inhibitors interacted synergistically and significantly decreased growth compared to PARP inhibition alone.…”

Section: Targeting Pi3kmentioning

confidence: 99%

Systemic therapy options in BRCA mutation-associated breast cancer

Bayraktar

Glück

2012

Breast Cancer Res Treat

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Section: Targeting Pi3kmentioning

confidence: 99%

Systemic therapy options in BRCA mutation-associated breast cancer

Bayraktar

Glück

2012

Breast Cancer Res Treat

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“…Recent preclinical data have shown a possible synergism between PARP inhibitors and PI3K inhibitors in breast cancer cell lines with or without BRCA1 and/or PTEN treated with this compounds [Kimbung et al 2012]. In this study, the administration of PARP inhibitors caused DNA damage by conferring G2/M arrest and decreased viability with an increase of apoptosis.…”

Section: Egfr Inhibitorsmentioning

confidence: 59%

Triple-negative breast cancer: are we making headway at least?

et al. 2012

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Abstract:The so-called triple-negative breast cancer, as defined by tumors that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression, has generated growing interest in recent years despite representing less than 20% of all breast cancers. These tumors constitute an important clinical challenge, as they do not respond to endocrine treatment and other targeted therapies. As a group they harbor an aggressive clinical phenotype with early development of visceral metastases and a poor long-term prognosis. While chemotherapy remains effective in triple-negative disease, research continues to further identify potential new targets based on phenotypical and molecular characteristics of these tumors. In this respect, the presence of a higher expression of different biomarkers including epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and Akt activation has led to a proliferation of clinical trials assessing the role of inhibitors to these pathways in triple-negative tumors. Moreover, the described overlap between triple-negative and basal-like tumors, and the similarities with tumors arising in the BRCA1 mutation carriers has offered potential therapeutic avenues for patients with these cancers including poly (ADP-ribose) polymerase inhibitors and a focus on a higher sensitivity to alkylating chemotherapy agents. Results from these trials have shown some benefit in small subgroups of patients, even in single-agent therapy, which reflects the heterogeneity of triple-negative breast cancer and highlights the need for a further subclassification of these types of tumors for better prognosis identification and treatment individualization.

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“…When combined with NVP-BKM120 and olaparib tumor doubling was delayed to more than 70 days in the mouse model and more than 50 days in xenotransplants from human BRCA1-related tumors indicating that the combination of a PI3K inhibitor with a PARP inhibitor provides a new trend of combination to be tested in clinics for BRCA1-related BC. In BRCA1-deficient breast cancer cells co-targeting of the PI3K pathway was reported to improve the response of to PARP1 inhibition by Kimbung et al [78]. In their study, a sequential combination of PARP and PI3K inhibitors interacted synergistically to significantly decrease growth compared to PARP inhibition alone.…”

Section: Parp Inhibitors As Chemo/radiopotentiating Agents: Tnbc and mentioning

confidence: 99%